ABSTRACT Sjgren's syndrome (SjS) impacts several million people annually in the US, with women being nine times more likely to be affected than men. To date, no vaccine or therapeutic exists to cure SjS, and patients must rely on lifelong therapies to treat symptoms. While a few studies have examined the types of regulatory T and B cells (Tregs and Bregs) induced by SjS, none have addressed how Treg plasticity impacts disease resolution. To address this shortcoming, we propose that the use of a broad-based immunotherapeutic capable of eliciting regulatory cells can resolve SjS. Colonization factor antigen I (CFA/I) fimbriae from enterotoxigenic E. coli, when given nasally or orally, terminates disease progression. To facilitate its mucosal delivery, we successfully expressed the cfaI operon in Lactococcus lactis (L. lactis-CFA/I), and it potently suppressed inflammation in mice induced experimentally with rheumatoid arthritis and multiple sclerosis. These fimbriae are presumed to act by inducing infectious tolerance, resulting in the stimulation of antigen-specific regulatory T cells (Tregs) that produce IL-10, IL-35, and TGF-b. Such bystander immunity does not render global immunosuppression, and adaptive immunity are sustained in these animals. When tested in a spontaneous, genetically defined murine SjS model, 28 wk-old diseased mice showed remarkable recovery in their salivary flow following treatment with L. lactis-CFA/I. Treg analysis revealed a significant increase in Foxp3+ Tregs producing TGF-b and some IL-17-producing Tregs in combination with IL-10. In addition, an increase in IL-10-producing B cells was found implicating the induction of Bregs as well. Concomitant reductions in IL-17- and GM-CSF-producing effector T (Teff) cells were also observed. Based upon these findings, the proposed studies will test the hypothesis that CFA/I fimbriae activate disease-specific Tregs and/or convert pathogenic T cells into Tregs, thus suppressing pathogenic CD4+ T cells. This suppression is accomplished via Tregs and Bregs producing TGF-b, IL-10, or IL-35 as well as by IFN-g- producing T-bet+ Tregs and/or RoRgt+ regulatory Th17 (Tr17) cells. To test this hypothesis, three Specific Aims are proposed. Studies in Specific Aim 1 will determine the types of Tregs and Bregs induced during SjS and will determine how L. lactis-CFA/I intervention at different disease stages, (e.g., early disease has inflammatory cell infiltration of submaxillary glands; late stage has auto-antibody production and reduced salivary flow), can augment these Tregs and Bregs. Studies in Specific Aim 2 will determine the relevance of Tregs subsequent to their adoptive transfer and cytokine neutralization, and will assess their impact upon auto-antibody production. Studies in Specific Aim 3 will determine whether CFA/I fimbriae-induced Tregs and Bregs synergize to suppress IL-21- producing follicular T helper (TFH) cells that promote auto-antibody production. These studies will provide the basis for future testing in SjS patients.